5-fluorouracil (hereinafter referred to simply as 5-Fu), which is one of the active compounds used in this invention, is a commercially available antitumor agent which is used for treatment of tumors in the digestive organs through peroral administration in the form of an aqueous solution. However, 5-Fu absorbed through the stomach wall tends to amass not only in the tumor site but also in the bone marrow, so that it may cause myeloid trouble. For this reason, the dosage of this medicine is limited although the effect thereof is considerably sacrificed by such limitation. A strong request is therefore voiced in the art for the development of a method which is capable of effecting as much absorption of the medicine into the tumor site as required for tumor treatment while minimizing amassing of the medicine in the bone marrow.
Bleomycin and bleomycin derivatives are also known to have the antitumor activities as for instance disclosed in U.K. Pat. No. 1,038,242, U.S. Pat. No. 3,846,400 and U.S. Pat. No. 3,922,262. However, such bleomycins are scarcely absorbed through the gastroenteric wall, so that the commercially produced bleomycins are exclusively used as injections. Since bleomycins have the inclination to be selectively absorbed into the tumor sites such as skin cancer, head and neck cancers (such as cancer of the upper jaw, cancer of tongue, cancer of lip, laryngeal cancer, etc.), esophagus cancer of squamous epithelium), cervix cancer, malignant lymphoma, glioma, etc., they are used by injection for treatment of these tumors. However, if such bleomycins can be selectively absorbed into the tumors in the digestive organs such as gastrointestinal organs, they can as well be used for treatment of such tumors, so that the development of a method for allowing selective absorption of bleomycins into such tumors is wished.
In the course of extensive studies on this subject, the present inventors have noted quite unexpectedly the facts that when 5-Fu, bleomycin or a bleomycin derivative is peroally administered along with a polyacrylic acid alkali metal salt to the rate having experimentally transplanted gastrointestinal tumors, the concentration of said active compound in the tumors becomes higher than when an aqueous solution of such compound is administered peroally or by subcutaneous injection, and such high concentration is maintained for a long time, in other words, the absorption of said compound is administered peroally or by subcutaneous injection, and such high concentration is maintained for a long time, in other words, the absorption of said compound into the tumors is selectively enhanced to markedly arrest growth of the experimental tumors, and particularly in the case of 5-Fu, the side effects such as myeloid trouble are strikingly suppressed. The present invention was completed on the basis of such findings.
Applications of alkali metal salts of polyacrylic acid as an adjuvant for the medicinal compositions are noted in Australian Pat. No. 256,852 and Japanese Pat. Laid-Open No. 142523/1976. Australian Pat. No. 256,852 discloses a composition comprising tetracycline antibiotics and a hydrolyzed polyacrylonitrile, a polyacrylic acid or salts of any of these compounds for enhancing absorption of tetracycline antibiotics from the stomach and intestines and also elevating their concentration in the blood. Japanese Patent Laid-Open No. 142423/76 discloses a medicinal composition prepared by first forming small granules of a composition comprising the active compound and a water-soluble high molecular material (such as an alkali metal salt of polyacrylic acid, polyethylene glycol, etc.) which forms a highly viscous solution in the presence of water, and then coating these granules with a coating agent which is disintegrated in the stomach. This medicinal composition allows long-time intragastric retention of the medicine which produces strong potency when staying in the stomach for a long time, such as for example antiulcer drugs like antipeptic agents, penicillins, vitamins, etc.
However, none of these prior art literatures shows any disclosure suggestive of the peroral antitumor compositions of this invention comprising 5-Fu, bleomycin or a bleomycin derivative and an alkali metal salt of polyacrylic acid and the fact that such compositions are capable of selectively enhancing absorption of 5-Fu, bleomycin or bleomycin derivatives into the gastrointestinal tumor site.